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TP53 mutations emerge with HDM2 inhibitor SAR405838 treatment in de-differentiated liposarcoma
Joonil Jung1, Joon Sang Lee1, Mark A Dickson2
1Sanofi Oncology, Cambridge, Massachusetts 02139, USA.
Abstract:
In tumours that harbour wild-type p53, p53 protein function is frequently disabled by the mouse double minute 2 protein (MDM2, or HDM2 in humans). Multiple HDM2 antagonists are currently in clinical development. Preclinical data indicate that TP53 mutations are a possible mechanism of acquired resistance to HDM2 inhibition; however, this resistance mechanism has not been reported in patients. Utilizing liquid biopsies, here we demonstrate that TP53 mutations appear in circulating cell-free DNA obtained from patients with de-differentiated liposarcoma being treated with an inhibitor of the HDM2-p53 interaction (SAR405838). TP53 mutation burden increases over time and correlates with change in tumour size, likely representing selection of TP53 mutant clones resistant to HDM2 inhibition. These results provide the first clinical demonstration of the emergence of TP53 mutations in response to an HDM2 antagonist and have significant implications for the clinical development of this class of molecules.
Insights
Emergence of TP53 mutations in patients treated with HDM2 inhibitors was observed. These TP53 mutations in cell-free DNA indicate acquired resistance to HDM2 antagonists in de-differentiated liposarcoma.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Wild-type p53 tumor suppressor function is often inhibited by MDM2 (HDM2 in humans).
- HDM2 antagonists are in clinical trials for cancer treatment.
- TP53 mutations are a suspected mechanism of resistance to HDM2 inhibition, but lack clinical evidence.
Purpose of the Study:
- To investigate the emergence of TP53 mutations as a resistance mechanism to HDM2 inhibitors in patients.
- To provide the first clinical evidence of TP53 mutations arising during treatment with an HDM2 antagonist.
Main Methods:
- Utilized liquid biopsies to analyze circulating cell-free DNA (cfDNA).
- Monitored TP53 mutation status in patients with de-differentiated liposarcoma receiving the HDM2 inhibitor SAR405838.
- Correlated TP53 mutation burden with tumor size changes over time.
Main Results:
- TP53 mutations were detected in cfDNA of patients treated with the HDM2 inhibitor SAR405838.
- The burden of TP53 mutations increased over the course of treatment.
- Increased TP53 mutation burden correlated with tumor progression, suggesting selection of resistant clones.
Conclusions:
- This study provides the first clinical demonstration of TP53 mutations emerging in response to HDM2 inhibition.
- The findings highlight TP53 mutation as a clinically relevant resistance mechanism to HDM2 antagonists.
- Results have significant implications for the clinical development of HDM2 inhibitors in oncology.
